Dr. William Charini graduated from Princeton University and obtained his medical and doctoral degrees from the University of California, Irvine. Since completing his residency in Internal Medicine at Duke University and at Brigham and Women's hospital, he has been a Fellow at Infectious Diseases at the Beth Israel Deaconess Medical Center (BIDMC). He is committed to a full-time career as a medical scientist with a special interest in vaccine development and AIDS related immunology. Because CTL play an important role in containing HIV replication, an effective AIDS vaccine must elicit a potent HIV-specific CTL response. In studies employing the SHIV/macaque model, the mechanism of CTL epitope election will be explore with the objective of developing an AIDS vaccine that will elicit CTL specific for a broad diversity of epitopes. DNA immunization of rhesus monkeys will be used to elicit CTL specific for a genetically modified Gag protein of simian immunodeficiency virus (SIV). The modification include a deletion of alteration a well- characterized Mamu-A*01-restricted dominant CTL epitope. It is expected that immune presentation of the epitope deleted-or epitope- altered GAG proteins will result in a CTL response specific for non- dominant epitopes. These non-dominant epitopes will be mapped and characterized, using functional CTL assays, tetramer staining, binding assays and epitope-specific anti-MHC class I monoclonal antibodies, in order to understand why they do not elicit stronger CTL responses when presented together with the dominant epitope. In addition, the hypothesis that immunodominance is driven by competition among CTL for epitopes presented by the same antigen presenting cell will be tested. The proposed studies will also determine whether DNA immunization can elicit a CTL response specific for both dominant and non-dominant epitopes. Immunized monkeys that display broad CTL responses to dominant and non-dominant epitopes will be challenged with a pathogenic SHIV in order to test whether broad CTL immunity results in improved protection against infection. Dr. Norman Letvin, Chief of the Division of Viral Pathogenesis at BIDMC, will guide Dr. Charini's maturation as an independent investigator. Dr. Charini will complete graduate course work in immunology at Harvard Medical School to improve his scientific foundation for a career in vaccine development. In addition, a committee of distinguished scientists including two AIDS researchers and an immunologist, will oversee Dr. Charini's progress.